About 30% of drugs that appear on the World Health Organization (WHO) Essential Drug List were reported to be poorly water-soluble, based on the Biopharmaceutics Classification System (BCS). See, for example, Kasim, N. A., et al., Molecular properties of WHO essential drugs and provisional biopharmaceutical classification, Molecular Pharmaceutics 2004, 1(1): p. 85-96. Over 40% of newly developed pharmaceutically active substances have solubility issues. See Lipinski, C. A., Drug-like properties and the causes of poor solubility and poor permeability, Journal of Pharmacological and Toxicological Methods 2000, 44(1): p. 235-249. The poor dissolution and/or permeability of these drugs often results in low, but highly variable, bioavailability. Further, a major obstacle of successfully commercializing these compounds is the difficulty of enhancing their dissolution rate and extent of dissolution.
For example, abiraterone acetate is approved in the United States as an oral treatment for metastatic castration-resistant prostate cancer. The product insert describes abiraterone acetate as a lipophilic compound that is practically insoluble in water. See Zytiga™ Full Prescribing Information, 2012, Janssen Biotech Inc., Section 11. While the insolubility of abiraterone acetate allows for its preparation in capsule form for oral dosing, it precludes intravenous (IV) administration which is used for other treatments of prostate cancer, such as cabazitaxel. See Sartor, O. et al. The Oncologist 2011, 16: 1487-1497.
Due to its insolubility, abiraterone acetate suffers from low bioavailability that arises from poor absorption, as 77% of the administered drug is excreted. See Ratain, M. J. Journal of Clinical Oncology 2011, 29(30): 3958-3959). Thus, most of the administered drug is not used for its intended treatment.
The low water solubility of abiraterone acetate has led to a food-effect that is greater than any other marketed drug (five- to ten-fold, depending on fat content of the meal), and significant interindividual pharmacokinetic variability. This food-effect can also afford a large intraindividual variability, resulting in underdosing or overdosing. Thus, strict patient compliance is required to achieve the dosing under labeled conditions.
Further, abiraterone acetate is a substrate of the CYP3A4 liver enzyme, which can lead to potential drug-drug interactions with other administered drugs that inhibit or induce CYP3A4. See Zytiga™ Full Prescribing Information, 2012, Janssen Biotech Inc., Section 7.2.
The development of soluble abiraterone derivatives would allow for IV dosing, which bypasses the liver, and could alleviate some of the aforementioned problems.
Accordingly, there is a clear and continuing need to create more soluble forms of abiraterone.